Method for its preparation



Patented Aug. 29, 1950 7-HYDROXY-8METHYLISOQUINOLINE AND METHOD FOR ITS l REPARATION Robert B. Woodward, Cambridga'Mass and Wil- 11am von Eggers Doering, Katonah, N. Y., as-

UNITED STATES PATENT OFFICE signers to Polaroid Corporation, Cambridge, Mass, a corporation of Delaware N Drawing. Original application November 4,

1943, Serial No. 508,954. Divided and this application December 3, 1948, Serial No. 63,456

14 Claims. (Cl. 260289) This invention relates to the formation of compounds useful in the synthesis of quinine and cinchona alkaloids and more particularly to 7- hydroxyisoquinoline derivatives and to methods of preparing the same.

This application is a division of our copending application Serial No. 508,954, filed November 4, 1943, for a patent for 7-Hydroxyisoquinoline Derivatives and Methods of Preparing the Same,

The 7 hydroxy 8 N- nOW Patent 2,475,932, issued y 1 49- 10 aniline, is 7-hydr0xy-8-methyl-anilinomethyliso- Object of the present e iml s to pr quinoline; of a mixture including methylamine, -Q novel y Y S q derivatives is 7-hydroxy-8-methylaminomethylisoquinoline; hav ng, or being transformable to compounds of mixture including dimethylamine is 7. 1. having the skeleton: droxy-8-dimethylaminomethylisoquinoline; of a o mixture including piperidine is 7-hydroxy-8- o piperidinomethylisoquinoline; and of a mixture 1 /g\ including morpholine is 7-hydroxy-8-morpho- N2 0 7C linomethylisoquinoline.

a t at substituted aminomethylisoquinolines may be g 2 separated from the reaction product and purified in any conventional manner.

Another ob ect is to provide a novel method of A novel method of purifying synthteslzntg h above compounds from piperidinomethylisoquinoline is to react said compound with an excess of sodium hydroxide to A further ob ect 1s to prov1de a novel method form the sodium salt thereof, said salt being subofoformmgh7'hydmxy's'tnethyhsoqumolme' stantially insoluble in the sodium hydroxide sog g ffi g gi fi igigfifi g g ig s z i ffig lution formed by the excess of sodium hydroxide. droxyisoaumolme w formaldeh de a The salt can be readily crystallized and the 7-hyy droxy- 8 piperidinomethylisoquinoline regenercomposition from the class consisting of primary ated therefrom by acidification and secondary amines, these ingredients being preferably mixed in a hydroxylic solvent, such as ethanol, methanol or water, or in a mixture of said solvents, as for example aqueous ethanol or aqueous methanol. The formaldehyde may be obtained from any suitable source and may be 0 conveniently introduced into the reaction mixture in aqueous solution. The primary or secondary amine may, for example, be any one of the following: piperidine, morpholine, aniline and its homologues, and the alkyl and dialkyl amines, such .as 'methylamine, ethylamine, dimethylamine, diethylamine,. methylethylamine, propylamine, dipropylamine, methylpropylamine, ethylpropylamine, butylamine,.as well as aryl substituted derivatives of said alkyl and of said dialkyl amines. The completely aromatic secondary amines, as for example diphenyl-amine and the. aromatic. heterocyclic amines, such as indole and thiazole, are less preferred than the nonaromatic heterocyclic secondary amines, such as morpholine and piperidine and the noncyclic amines having at least one alkyl group attached to the nitrogen, such as the alkyl and dialkyl amines.

The product of the above reaction comprises a ethylbutylamine, .isopropyl- To prepare 7-hydroxy-8-methylisoquinoline, any one of the 7-hydroxy-8-N-substituted aminomethylisoquinolines is reduced by being reacted with an alkali methoxide, such as sodium methoxide or potassium methoxide, preferably in a hydroxylic solvent, such as methanol. This reaction is preferably carried out in an autoclave and a preferred temperature and time range therefor is between 200 and 250 C. and from six to sixteen hours. The reaction products comprise the alkali salt, e. g., the sodium 01' potassium salt, of '7-hydr0xy-8-methylisoquinoline and said salt'is neutralized by acidification to free the 7 hydroxy 8 e methylisoquinoline, the latter compound being thereafter isolated from the reaction products, preferably by sublimation and crystallization.

One method of purifying the 7-hydroxy-8- methylisoquinoline is by forming the oxalate of said compound, crystallizing said oxalate, and then acidifying the same to regenerate the pure '7-hydroxy-8-methylisoquino1ine.

7 An alternate, and for commercial production, a preferred method of obtaining the novel '7-hydroxy-8-methylisoquinoline is to react the prodquinoline.

nets of the initial reaction, i. e., the reaction products of formaldehyde, 7-hydroxyisoquinoline and the primary or secondary amine directly with the alkali-e-methoxide, without rfiISt dselating the 7hydro)??-8Nsulastituted aminomethyliso The 7-hydroxy-8-methylisoquino1ine is thereafter obtained, isolated and purified, as-

above described.

The following examples are-given -to illustrate substituted aminomethyl derivative of '7 -hydroxyisoquinoline, 7-hydroxy-8-pip,eridinomethylisoquinoline. Example 2 illustratesthe prepara-' tion of 7-hydroxy-8-methylis'oquinoline fromvthe 7-hydroxy-8piperidinomethylisoquinoline of Example l. thesis of 7-hydroxy-8-methylisoquinoline from 7- hydroXyisoquinol-inewherein the se'N substituted a-mi-nozn'ethylderivative: is not: isolated prior to rednctiom Example 1 is filtered and from it the. desired; material is regenerated by neutralizing with acid and ex tra'eti'ng with ether The:oil left onzevaporation of thei ether is dissolvedin" boiling hexane. The clear? solution. depositslibrilliant' prisms or. Whydroxy+8 piperidinomethylisoq-ninoline, having". a melting point of front 8 l25 tol8215 C;

Example" 2.

Twelve grams of sodium metal i's dissolvedin 190i c'c:. of absolute? methyl a'lcohol'=.-. Ten grams of: '7=hydroxy 2%-piperidinomethylisoqu-inoline in 58 cc; ofaa'bsolutemethyl'alcoholis a'ddediand-the sdlutiohiSh-eated'for sixteen' hoursrat 220*-C'.

inethe-autoclave.

Water and hydrochloric acid? areadded tothe reaction solution an'dithe methanolis boiled off. On bufferingwith 'so'dium carbonate solution; 5.1

1 grams-of, crude product is obtained.

Sublimation of the.-.crude="7-hydroxy 8-methylisoqn-inoline' gives hZ i grams of pure material havingaumeltingnpointof from-229 to 231 C.

7 Example, 3

Twenty grams-=05 '7-hydroxyisoquinoline is-..dis

solved in 590* cc; of boiling methanol containing grams? of pipe ridine is adder-1; 14; grams. of? 35% Eorma-li-n solution.

To the cooled solution A-iten standing fortwo and one h-alf" hou-rs at roam-temperature; the solvent is blown ofiand'the residual oil is-driedin vacuo.- The dried oil'is takennp in 550 cc. ofabsolute methanol and =l30 grams of: sodiummethox-ide is added; The solution is heated in the autoclave at 220 C. for twelve-hours I Thereaction mixture is; diluted-with 400' cc. of water -and partially neutralized with 150 cc. of

concentrated hydrochloric acid. The solution is boiled down to 400 '00. at which time 300 cc. additional watervis added and boiling is continued till-,the vapors no longer-burn. The. cooled solution-isneutralized withhydrochloric. acid and Example l illus Example 3 is illustrative of thesyn buffered with sodium bicarbonate. The precipitate of 7-hydroxy-8-methylisoquinoline is collected and dried.

Thercrudamaterialisasubl-imedand the subli'niate is dissolved. in 400500.- of methanol. After concentrating the solution to 200 cc. and cooling, 19.3 grams of shiny platelets, having a melting point of from 230 to 232 C'., is obtained.

Since'certai'rrchanges in carrying out the above methodsand in obtaining the various species of the-inventionmay. be made without departing from the-'scope -thereof, it is intended that all mattercontained-in: the above description shall be interpreted as-.-i-l lustrative and not in a limiting sense.

What is: claimed; is:

1 Asanew; composition, 7-hydroxy-8-methyL isoquinoline.

2i The-method of producing a '7-hydroxy-8- methylisoquinoline which comprises reducin by reaction with an alkalieimethoxi'de a". T hyd 'roxy- 8=N-sub'stituted'-'-'- aminometliylisoquinolinez 3; The method of producing 7-hy'd-roxy fi methylisoquinoline whicin comprisesreducing by reaction with an alkali methoxide'afl hydroxy s euiistituted isoquinoline -havi-ng -attachedtto the eight position-ofthe' isoquiholine "skeletonthe group, CH2R;- wherein R r epresentsasaturat'ed N=hete rocyclic radical;

The method oiproducing '7-h-ydroxy-B methylisoquinolir'ie which comprises reacting-- an alkali methox id e" a 7-'-hydroXy-8'-N'-substituted aminomethylisoquinoline attached to the eight position of the isoquinoli ne skelet'on teob tain the alkali saltzof 'Z-hydroxy-S-methylisoquinoline, and reacting said salt with an acid to obtain the '7-hydroxy=8.-methylisoquinoline.

5. The method: of producing 7-hydr0Xy-8- methylisoquinoline which com-prises reacting an alkali methoxide with: a '7-hydroxy-S-substitutedisoquinoline having attached to the eight position" of the isoquinol-in'e skeleton the group, -CH2--R;' wherein Rf represents a saturated N= heterocyclic radical, to obtain the alkali-salt of 7-hydroxy-8 methyl'isoquinoline, and reacting said saltwith anacidto'obtainithe 7-hydroxy.,-8= methylisoquinoline.

6. The method of; producing. 7-hydrox'y -8"- methylisoquinoline which comprises reacting sodium methoxide' in a hydroxylics'olvent in a pressure vessel at a" temperature of from 200 to v250" C. for from sixtosixteen"hoursiwithia 7-hyd'roxy'= 8"-N=substituted-aminomethylisoquinoline, tov obtain the sodium" salt of' '7;hydroxy-8-'methy lisoquinoli'ne, ,and neutralizing saidsalt by reacting the samewith an acidftolobtain the 'T-liydroxy-ST- methylisoquinoline. 7

'7. The method of producing WhydrOXy-BP methylisoquinoli'ne which comprises reacting so: diu'n'i methoxidein ahydro-Xylic'solventin agpressure vesselat temperature of from 2l00"to, 250. C. for, from sixtosixteeh hours'with aJIi-hyd'roxyjr 8substitutedsisoquinoline haying-attachedto the eight position of the. isoquinoline skeleton. the group, CH2R, whereinR. .represntsasaturated Nheterocyclic radical, to obtain the. so..- diumsalt of. 'Z-hydicoxy-8'emethylisoquinoline, and neutralizing. said salt by. reacting. thesame with an acid, to: obtain the: 7-.hydroxy-8-methyli'soquinoli'ne- 8. The method of producing. 'T-hydroxy-8e methylisoquinoline which: comprises reacting.- so dium. methoxide. in ahydroxylic solvent in a .pres-. sure vessel at a temperature aof-irom 200 M2595 C...for-.from six-to sixteemhoursawithfl hydroxy- 8-piperidinomethylisoquinoline to obtain the sodium salt of '7-hydroxy-8-methylisoquinoline, and reacting said salt with an acid to obtain the '7-hydroxy-8-methylisoquinoline.

9. A method of producing 7-hydroxy-8-methylisoquinoline which comprises reacting 7-hydroxyisoquinoline, formaldehyde and a compound from the class consisting of primary and secondary amines, reacting the products of said reaction with an alkali methoxide to form a product comprising the alkali salt of '7-hydroxy-8-methylisoquinoline, reacting said salt with an acid to free the Z-hydroxy-8-methylisoquinoline, and isolating the latter compound by sublimation and crystallization from the remaining reaction products.

10. The method of producing 7-hydroxy-8- methylisoquinoline which comprises reacting 7- hydroxyisoquinoline, formaldehyde, and a saturated, heterocyclic amine, reacting the products of said reaction with an alkali methoxide to form a product comprising the alkali salt of 7-hydroxy- 8-methylisoquinoline, reacting said salt with an acid to free the '7-hydroxy-8methyliso uinoline, and isolating the latter compound by sublimation and crystallization from the remaining reaction products.

11. A method of producing 7-hydroxy-8-methylisoquinoline which comprises reacting l-hydroxyisoquinoline, formaldehyde and a compound from the class consisting of primary and secondary amines, reacting the products of said reaction with a compound from the class consisting of sodium methoxide and potassium methoxide to form a product comprising the corresponding alkali salt of 7-hydroxyS-methylisoquinoline, reacting said salt with an acid to free the 7- hydroxy-8-methylisoquinoline, and isolating the latter compound by sublimation and crystallization from the remaining reaction products.

12. A method of producing 7-hydroxy-8-methylisoquinoline which comprises reacting q-hydroxyisoquinoline, formaldehyde, and a saturated, heterocyclic amine, reacting the products of said reaction with a compound from the class consisting of sodium methoxide and potassium methoxide to form a product comprising the corresponding alkali salt of 7-hydroxy-8-methylisoquinoline, reacting said salt with an acid to free the 7-hydroxy-8methylisoquinoline, and isolating the latter compound by sublimation and crystallization from the remaining reaction products.

13. A method of producing 7-hydiOXY-8-ll1fillhylisoquincline which comprises reacting 7-hydroxyiscquinoline, formaldehyde and a compound from the class consisting of primary and secondar amines, reacting the products of said reaction with an alkali methoxide in a hydroxylic solvent in a pressure vessel at a temperature of from 200 to 259 C. for from six to sixteen hours to form a product comprising the corresponding alkali salt of '7-hydroxy8-methylisoquinoline, reacting said salt with an acid to free the Phydroxy-B-methylisoquinoline, and isolating the latter compound by sublimation and crystallization from the remaining reaction products.

14. A method of producing 7-hydrcxy-8-methylisoquinoline which comprises reacting 7-hydroxyisoquinoline, formaldehyde, and a saturated, heterocyclic amine, reacting the products of said reaction with sodium methcxide in a hydroxylic solvent in a pressure vessel at a temperature of from 200 to 250 C. for from six to sixteen hours to form a product comprising the sodium salt of '7-hydroxy-8-methylisoquinoline, reacting said salt with an acid to free the 7-hydroXy-8-methylisoquinoline, and isolating the latter compound by sublimation and crystallization from the remaining reaction products.

ROBERT B. WOODWARD. WILLIAM VON EGG-ERS DOERING.

No references cited. 

1. AS A NEW COMPOSITION , 7-HYDROXY-8-METHYLISOQUINOLINE.
 9. A METHOD OF PRODUCING 7-HYDROXY-8-METHYLISOQUINOLINE WHICH COMPRISES REACTING 7-HYDROXYISOQUINOLINE, FORMALDEHYDE AND A COMPOUND FROM THE CLASS CONSISTING OF PRIMARY AND SECONDARY AMINES, REACTING THE PRODUCTS OF SAID REACTION WITH AN ALKALI METHOXIDE TO FORM A PRODUCT COMPRISING THE ALKALI SALT OF 7-HYDROXY-8-METHYLISOQUINOLINE, REACTING SAID SALT WITH AN ACID TO FREE THE 7-HYDROXY-8-METHYLISOQUINOLINE, AND ISOLATING THE LATTER COMPOUND BY SUBLIMATION AND CRYSTALLIZATION FROM THE REMAINING REACTION PRODUCTS 